DESCRIPTION: SIV infection of rhesus monkeys mimics many of the features of HIV induced disease in humans. The virus targets CD4+ T lymphocytes, viral replication is persistent despite an apparently strong host immune response and infection leads to gradual declines in CD4+ lymphocyte concentrations and death. The long-term goal of the proposed studies is to understand the molecular mechanisms of AIDS disease process in as great detail as possible using the experimental SIV system. The current proposal focuses on the role of the nef gene and the need for lymphocyte activation for viral replication. Recent studies from this investigator's laboratory suggest that Nef may activate signal transduction pathways causing lymphocyte activation and thus greatly facilitate virus replication in vivo. To obtain more definitive evidence for the role of Nef in viral infection, the following specific aims are proposed: Specific Aim 1: To relate SIV Nef sequence to function. Specific Aim 2: To select HIV variants that cause lymphocyte activation. Specific Aim 3: To investigate the mechanisms of Nef-induced lymphocytes activation. Specific Aim 4: To provide in vivo evidence for Nef-induced lymphocyte activation.